Certain alpha (1-diethylaminoethyl) benzimidazolyl (2), alpha-aryl acetamides



United States Patent CERTAIN ALPHA (I-DIETHYLAMINOETHYL) BENZIMIDAZOLYL 2 ALPHA-ARYL Ac- -ETAMIDES Karl Hoifmann, Binningeu, and Alfred Hunger, Basel,

Switzerland, assignors to Ciba Pharmaceutical Produc'ts Iuc., Summit, NJ., a firm No Drawing. Filed June 19, 1958, Ser. No. 143,005

Claims priority, application Switzerland July 17, 1957 6 Claims. c1. 260-3092) The present invention relates to a-ll-(lower tertiary amino-lower alkyl) -benzimidazolyl-( 2) l-a-phenylacetam ides'and to their salts. The invention relates particularly to benzimidazolyl compounds of the formula in which A represents a lower alkylene radical, more especially ethylene, and R represents a lower alkyleneimino group which may be interrupted by a hetero atom, such as a piperidino, pyrrolidino or morpholino group, and more especially a di-lower alkyl-amino group, above all the diethyl-amino group, in which formula R is a phenyl radical which is unsubstituted or substituted in the 3-position and/or the 4-position, more especially in the 4-position, by halogen or a lower alkyl or lower alkoxy group, and their salts.

The new compounds have good analgesic action and can thus be used as analgetics.

Particularly valuable are the acetamides of the formula benzimidazole ring of an a-benzimidazolyl-(Zyet-phenylacetamide either directly or by stages. In this manner an u-benzimidazolyl-(2)-a-phenylacetamide can be reacted with a reactive ester of an-alcohol of the formula in which A has the meaning defined above and R represents a lower tertiary amino group, or a radical convertible into such group, e.g. a hydroxyl group, and in the resulting compound containing a radical convertible into a lower tertiaryamino-lower alkyl group said radical is so converted, for example a hydroxyl group by chlorination and subsequent reaction with a secondary amine. Reactive esters are more especially those of strong inorganic or organic acids such as those of hydrohalic acids or organic sulfonic acids, such as para-toluenesulfonic' acid. The introduction is preferably performed in the presence of a condensing agent, more especially one that is capable of forming metal salts with a-benzimidazolyh (2)-d-phenylacetamide, such as the alkali or alkaline earthmetals, for example sodium, lithium,calcium, their amides, hydrides, hydrocarbon compounds, alcoholates, oxides or hydroxides, e.g. sodamide, sodium hydride, sodium oxide or hydroxide, lithium butyl, potassium phenyl, lithium phenyl, potassium tertiary butylate or potassium tertiary 'amylate, or with the use of themeformed metalsalts of the benzim-idazole compound.

According to another process the benzimidazole ring substituted by a phenyl-carbamyl-methyl radical in the 2-position is formed by subjecting to ring closure an ortho-(YNH)-aniline or a suitably N-substituted derivative thereof, in which Y represents a lower tertiary amino-lower alkyl group or a radical convertible thereinto, such, for example, as the ,B-chloroethyl group. The radical convertible into the lower tertiary amino-lower alkyl group is then' subsequentl converted into this group; in the case of the S-chloroethyl group, for example, this is achieved by reaction with diethylamine. In this manner an ortho-(lower tertiary amino-lower alkylamino)-aniline can be subjected to direct or stepwise ring closure with an u-carbamylphenylacetic acid or with a reactive functional derivative thereof, more especially an ester with an alcohol that is easily to split oif or with an imino ether. To prepare the final products of the present process it is also possible to condense with a phenyl-acetaldehyde or a functional derivative thereof instead of with a phenylacet-ic acid, the product formed then being oxidized. V

Alternatively, the new compounds are obtained when in a l-(lower tertiary amino-lower alkyl)-2-benzyl-benzimidazole a radical attached to the aliphatic carbon atom of the benzyl radical and convertible into a carbamyl group is so converted. A'radical convertible into a carbamyl group is, ,for example, a free or reactive functionally converted carboxyl group, more especially an acid halide group, an acid ester group or nitrile group. The conversion is conducted in usual manner, eg by treatment with ammonia or with a primary or secondary amine, or by hydrolysis respectively.

Substituents in the phenylor benzimidazolyl radical of the products of the invention can be replaced by other groups for instance a hydroxy group by an etherified hydroxy group or a hydrogen atom by a nitro group.

There-actions accordingto the present invention are performed in the presence or absence of a diluent and/ or condensing agent, if necessary at an elevated temperature, under atmospheric .or superatmospheric pressure.

According to the reaction-conditions employed the new compounds are obtained in the form of their free bases orof their salts. From the salts the free bases canbe made in a such known manner. The latter, by being reacted with acids suitable for theformation of--thera peutically useful salts, can be converted'into salts-,'j.fo r example salts of hydrohalic acids, sulfuric acid, nitric acid, phosphoric acid, thiocyanic acid, acetic acid, pro-- pionic acid, oxalic acid, malonic 'acid, succinic acid, malic acid, methanesulfonic acid, ethanesulfon-ic acid,

. hydroxyethanesulfonic acid,'benzenesulfonic or toluene sulfonic acid or of acids having therapeutic-action.

knownmethods. 1

The invention further includes those modificationsof the process in which the starting material is acom P atented July 5, 1960 ingmaterial,canbe prepaired'as'iollows:

-tion mm a m x g id? mererenn a ui euianerir melt poundiobtained. as. product at anystage V H of the process, and the remaining stage or stages are carried out. The new compounds can be used as medicfin the, form; of-vphamiace ticalaprepara i n Q0111 their salts inconjamct-ien; :a pharma:

ceutical organic inorganic, or; liquid; excipient suitable? for enierah parenteral or topical application.

', Theiexcipieni: is :madefi'om substances that do not-react with thetnewlcompounds; such, ior; fiamplepas water,

gelatine; lactose, starches; .stearate, talc;

vegetable oils; benzy1..gums; :polyalkylene glybenzimidazolyl ffl l w- (para-chlorophenyii is obtained in colorlesscrystals melting'a'td89 f9ll" C. r

cols,--white p'e'troleurnijellyrcholeste'rol"orother known 7 V medicinalexcipients," Iihehpharmaceutical preparations; a

ointmerfts, "creams liquid (solutions susicr' emulsionsli: *Theyzmray be-tste'rilized and/ or contain assistants; :such'la's; preservatives, stabilisers, Wetting; agent'sror emulsifiers, :for controllingtheaos'mofic 'pl'esslim-foifi If-desired,fthey mayfaisocontam' f mtherflmrapeutically'usefuhsubstancesi r inmfolie wing'mplesillustratetheinventioh.

' 858" gram sodami "de' dre enteredportiom wise intqa stirred' suspensionof fll grams-'of-a-benzimjd az1y1=rzy hsnyn eimiae:a 509 cc. ofi -absolute di- V 4 a 7 Example},

When the reaction described in Example 1 is performed with a-benzimidazolyl-(2)-a1(para-chlorophenyl)-acetamide, instead of withu-bgnzimidazolyl-(2)-a-phenylacetamidei an h w r i sfl n s r n m d un e o h ise identic onitions;tfi le( adicsy a iinmy qace'tamide s y rechleride r p re melts at N ta-117.57

The u-benziniidaml 1 reasetpsij" ananmtmide usedgas material be prenared'as V Ina descending condenser, closed, with a, calcium chloride I tube,. are mixedt'ogether 'sodium alcoholate prepared; from 24 grams of sodium, 200cc. of absolute toluene, l5 2' gfrarns parachlbrdhenzyl cyaifide of methyl: carbonate; The naixture is tlien a distillation while beingstirred, and settle-same toluene (total 690 cc} is added dropn'rise; with the dis tillation temperature rising from 801 to 110 C. When all the toluene has been added the mixture is stirred V tracted with ether, the ethereal solution is washed with.

isliberate'd; 1 in sage? s0 ofdiefllyl are fliendropped in, and the whole is for" 12 hoursatj the saine temperature.

residual 'soda'mideisj destroyed by "the dropwise addition of glacial acetic acid. reaction isthen evaporated yacuo, the residue is taken up swim e'ther; was hydrochloric acid s lu i render in s jNa drqcmoric cia and the solution is extracted alkaline with aqueous -ammonia andextra'cted'wich chloroform. "The chloroform extract is washedwit'h' sodium carbonate solution, dried over magnesium sulfate and eyaporated. Crystallization from ether yieldsu-Il- (fliet y mi o hy lnzimida lyl:t )i q -t ph nyldream" mum former colorless crystals meltingat issuer-c.

r Thehydrochlorideis ohtainedbyadding-ethanolic'lrydro-V chloric acid'to aniethanoli'c solution ofthe-base, evaporation andcrystallization froma mixtureof ethanol'and acetone; it melts unsharpiy at 150-160 v :C. a-Benzimidazolyl (2)-a-phenylacetaniidemsedas stare ingcolorless "crystals melting anaemic "C;

centrated sulfuric acid; 1-;After haying been kept for 1 16 hot melt is dilntedwith ethylene glycol monoethyl ieflicr; 1

for 2 hours at 110 (2' After cooling, ice water istadded the reaction mixture is filtered, and aqueous solution is immediately neutralized with glacial acetic acid, ex-

water, dried with magnesium sulfate, evaporated, and the residue is distilled under 0.12'mm. Hg pressure. The resulting product is para-chlorephenyicyanoacetic acid ethyl esterat 113420? C; underOJZ mm. I

pressure 7 v r 1 grams bff crthmphenylenediamme and"1-1zgrams'pf parwchlcrophenyl cyaneacetie acid ethyrester are heated in a flaskequippedwith a descending conden'serat- ZOG" Ci until nc more-ethanola'nd water pass over. a The sue'tibned'ofiand washed with ethanol and ether; 80 grams of benzimidazolyl-(2) -para-.ch1oropheny1 acetonitrile in colorlesscrystalsn elfing at 2044010. nitrile is hydrolyzed as described in Example '1. The resulting u benfiniidazoly1=(2)*- paraxhlorcphenynacetamide melts at 224-232 C. I

Example} I The reaction according to Example 1 is performed with a-benzimidazolyl fl) a-(meta-methoxyphenyl) -acet- 7.2 r of 2(B-diethylamino-ethylamino)-5 nitranihours et- 25?; the-mixture ne ly stirredinto cooledaqueous-ammonia. The preeipitate; a-benzirnidazolyh (Zj-a -phehylacetamide, is filteredoif; after recrystalliza at 218 -219 C.'

v amide, instead of with a-benzimidazolyl-(2)-u-phenylacet-' amide, otherwise processing in identical manner, and oz- [1 (,B-diethylamino-ethyl)-benzimidazolyl-(2) l-a- (metamethoxyphenyl) -acetamide in-colorless crystals melting at 15 3 -154" C. is obtained; its hydrochloride, prepared'as described'inExample 1, melts at 162'164"C.'

r The vstarting material, u-benzimidazclyl-"(fi-u-(metamethoxyphenyD -acetamide, can be ,prepar'edjas follows:

54 :grams of ortho-phenylenediarnine and 109mm of' ineta met roxypl1fenyl cyanoacetic acidethyrester'are heated in a'flask'eqnipp'ed witha descendingcendenserat 200 C. unfil'no more "ethanoljandwaterpass'oyer. The melt crystallises on methanol being added and yields benzi= midazo1y1-( 2) -meta methoqryphenyliacetonitrile melting at 137-139" C; 30. grams thereofareheatedin.90.cc.'of' glacial acetic acid'and' 301cc. ofjconcentrated sulfuric acid for Zhours at Q, the cooled solution-is; "stirred into a cooledaqueou's' ammoniasollftion and the precipitate is suctioned off; The product thus-obtained in; colorless crystals is a u benzimidaz'olyl (2) .-'(-rneta= methoxypheiiyl) -acetamide melting' at "147448C4 f Eiampl 7' line hydrochloride and {90 ccsof glacial -acetic acidffare added at 'roon-i temperature 7 to the phenylmalonie acid 5 solute ethanol in 100 cc. of chloroform by introducing dry hydrochloric acid gas at O to 20 C., stirring for 16 hours at 25 C. and evaporation under diminished pressure, and the mixture is stirred for 20 hours at 40-45 C. The reaction mixture is evaporated in vacuo, the residue taken up in aqueous hydrochloric acid, the acid solution is washed with chloroform and rendered alkaline with ammonia solution, extracted with chloroform, and the chloroform extract is washed with sodium carbonate solution, dried over magnesium sulfate, and evaporated. Crystallization from acetone yields u-[1-(p3diethylaminoethyl) -5-nitro-benzimidazolyl- (2) l-a-phenylacetamide of the formula in the form of colorless crystals melting at 133-137 C. The hydrochloride is prepared by adding the calculated amount of ethanolic hydrochloric acid to an ethanolic solution of the base; it has a double melting point of IDS-115 C. and 140-160 C.

Example 5 7.2 grams of Z-(B-diethylamino-ethylamino)-5-nitraniline hydrochloride and 90 cc. of glacial acetic acid are added at room temperature to the 4-chlorophenyl-malonic acid monoamide imino ether hydrochloride obtained from 14.6 grams of a-(4-chlorophenyl)-a-cyanoacetamide and 4.3 grams of absolute ethanol in 100 cc. of chloroform by introducing dry hydrochloric acid gas at to 5 C., stirring for 16 hours at 25 C. and evaporating under diminished pressure. The whole is then stirred for 20 hours at 40-45 C. The reaction mixture is evaporated in vacuo, the residue taken up in aqueous hydrochloric acid, the acid solution is washed with chloroform and rendered alkaline with ammoniasolution, extracted with chloroform, and the chloroform extract is washed with sodium carbonate solution, dried over magnesium sulfate and evaporated. Crystallization from a mixture of acetone and ether yields a-il-(fi-diethylamino-ethyl)-5-nitrobenzimidazolyl-(2)] a [4'-chlorophenyl]-acetarnide in colorless crystals melting at 161-163 C. The hydrochloride, prepared by adding the calculated amount of ethanolic hydrochloric acid to an ethanolic solution of the base, melts at ISO-155 C.

Example 6 1 gram of a-[lXfi-diethylamino-ethyl)-benzimidazolyl- (2)1-a-phenylacetonitfile is allowed to stand for 44 hours at 25 C. in 5 cc. of concentrated sulfuric acid, then aqueous ammonia; Extraction with chloroform, drying over magnesium sulfate, evaporation and crystallization from ether yields a-El-(fi-diethylamino-ethyl)-benzimidazolyl-(Z)l-a-phenylacetamide melting at l36-137 C.

' oc-[l (,8 diethylamino-ethyl)-benzimidazolyl-(2)l-aphenylacetonitrile used as starting material can be pre' pared as follows:

69.6 grams of benzimidazolyl-(Z)-phenylacetonitrile ar suspended in 800 cc. of absolute dioxane, 8.6 grams of powdered sodamide are entered in portions, and the whole is boiled with stirring until no more ammonia is liberated. Thereupon, 40.0 grams of diethylamino-ethyl chloride are added dropwise at C., and the whole is stirred for 16 hours at 60 C. The reaction mixture is treated with glacial acetic acid, evaporated in vacuo, and the residue is extracted with aqueous hydrochloric acid, and the acid ethereal extract is rendered alkaline with concentrated ammonia. The solution is then extracted with chloroform, the chloroform extract washed with sodium carbonate solution, dried over magnesium sulfate and evaporated. The residue, crude u-[I-(B-diethyIamino-ethyI) benzimidazolyl]-m-phenylacetonitrile, is distilled at 210" C. under 0.1 mm. Hg pressure; the distillate crystallises from ether in the form of colorless needles melting at 106-108" C.

What is claimed is:

l. A member of the group consisting of benzimidazolylacetamides of the formula in which R stands for a member of the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy and R for a member of the group consisting of hydrogen and (2) J-(para-chlorophenyl) -acetamide.

6. Therapeutically acceptable acid addition salts of a- [1-( B diethylaminoethyl) -5-nitro-benzimidazolyl-(2) ]-aphenylacetamide.

No references cited.

UNlTE STATES PATENT armor QE'lllCATWN F CQEUHQN Patent No. 2344 062 July 5, 1960 Karl Hoffmann et al0 It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, line 60 for "in a such" read in as such column 3 lines 45 to 48,, the right-hand portion of the formula should appear as shown below instead of as in the patent:

coNH

column 4 line 67, for "is a read is column 6 lines 31 to 34 the right-hand portion of the formula should appear as shown below instead of as i the patent:

Signed and sealed this 23rd day of May 1961a (SEAL) Attest:

ERNEST W SWIDER DAVID L; LADD Attesting Officer Commissioner of Patents 

1. A MEMBER OF THE GROUP CONSISTING OF BENZIMIDAZOLYLACETAMIDES OF THE FORMULA 